ABSTRACT
BACKGROUND/AIMS: Parkinson's disease (PD) is a prevalent disease that leads to motor and cognitive disabilities, and oxidative stress (OS) injury was found to be related to the etiology of PD. Increasing evidence has shown that SHC3 is aberrantly expressed in neurons. The current study examines the involvement of SHC3 silencing in OS injury in the nigral dopamine neurons in rats with PD via the PI3K-AKT-FoxO signaling pathway. METHODS: To study the mechanisms and functions of SHC3 silencing in PD at the tissue level, 170 rats were selected, and a lentivirus-based packaging system was designed to silence SHC3 expression in rats. Furthermore, PC12 cells were selected for in vitro experimentation. To evaluate the effect of SHC3 silencing in nigral dopamine neuronal growth, an MTT assay, propidium iodide (PI) single staining and Annexin V-PI double staining were performed to detect cell viability, cell cycle progression and cell apoptosis, respectively. RESULTS: SHC3 shRNA led to decreased SOD and MDA levels and enhanced GSH activity, indicating that SHC3 silencing leads to motor retardation. SHC3 silencing repressed the extent of Akt and FoxO phosphorylation, thereby inhibiting the PI3K-AKT-FoxO signaling pathway. Furthermore, in cell experiments, SHC3 silencing suppressed PC12 cell proliferation and cell cycle progression, whereas it enhanced cell apoptosis. CONCLUSION: The current study provides evidence suggesting that SHC3 silencing may aggravate OS injury in nigral dopamine neurons via downregulation of the PI3K-AKT-FoxO signaling pathway in PD rats.
Subject(s)
Dopaminergic Neurons/metabolism , Oxidative Stress , Signal Transduction , Src Homology 2 Domain-Containing, Transforming Protein 3/metabolism , Animals , Behavior, Animal , Disease Models, Animal , Forkhead Transcription Factors/metabolism , Lentivirus/genetics , Male , Malondialdehyde/metabolism , PC12 Cells , Parkinson Disease/metabolism , Parkinson Disease/pathology , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , RNA Interference , RNA, Small Interfering/metabolism , Rats , Rats, Sprague-Dawley , Src Homology 2 Domain-Containing, Transforming Protein 3/antagonists & inhibitors , Src Homology 2 Domain-Containing, Transforming Protein 3/genetics , Superoxide Dismutase/metabolismABSTRACT
High fructose consumption leads to metabolic syndrome and enhances cardiovascular disease risk. However, our knowledge of the molecular mechanism underlying the cardiac disease caused by fructose feeding is still poor. Nod-like receptors (NLRs) are intracellular sensors, responding to a variety of intracellular danger signals to induce injuries. NLRP4 is a negative regulator of nuclear factor-κB (NF-κB) signaling pathway through interactions with kinase IκB kinase (IKK). Here, we illustrated that NLRP4 attenuates pro-inflammatory cytokines releasing, including Transforming growth factor (TGF-ß1), Tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), interleukin-18 (IL-18) and interleukin-6 (IL-6), in fructose-treated cardiac cells by means of RT-qPCR, and western blotting analysis. In addition, NLRP4 could reduce the expression of TANK-binding kinase 1/interferon regulatory factor 3 (TBK1/IRF3), reducing inflammation response and achieving its anti-hypertrophic action. TBK1 plays critical roles in the IRF3 signaling pathway, modulating inflammation response. The inhibition of IKK/NF-κB signaling pathway by NLRP4 is confirmed by NLRP4 over-expression and knockdown. In vivo, high fructose feeding induced cardiac injury, accompanied with reduced expression of NLRP4 in heart tissue samples, indicating the possible role of NLRP4 in ameliorating heart injury. In conclusion, the findings above indicated that NLRP4 is an important mediator of cardiac remodeling in vitro and in vivo through negatively regulating TBK1/IRF3 and IKK/NF-κB signaling pathways, indicating that NLRP4 might be a promising therapeutic target against cardiac inflammation.
Subject(s)
Heart Injuries/chemically induced , Heart Injuries/metabolism , Ubiquitin-Specific Proteases/metabolism , Adaptor Proteins, Signal Transducing , Animals , Cell Line , Cytokines/metabolism , Down-Regulation , Feeding Behavior , Fructose , Gene Knockdown Techniques , Heart Injuries/genetics , Inflammation Mediators/metabolism , Mice, Inbred C57BL , Muscle Cells/metabolism , Myocardium/pathology , Rats , Signal Transduction , Ubiquitin-Specific Proteases/geneticsABSTRACT
The electronic contribution to thermal conductivity is studied in models of underdoped cuprates where the normal state has a pocketed Fermi surface with circumference â¼x (hole concentration) and the superconducting state is formed by opening a gap in the Fermi pocket. The physical consequences of the Fermi pocket are studied by comparing the thermal conductivity computed in four different models: (1) an ordinary d-wave superconductor with four Dirac Fermi points; (2) a normal metal with a pocketed Fermi surface; (3) a superconductor formed by spinon-holon binding in the t-J model; (4) a phenomenological d-wave Bardeen-Cooper-Schrieffer (BCS) superconductor with superconductivity formed by opening a gap on the pocketed Fermi surface. Our results suggest that thermal conductivity provides useful information to distinguish between different scenarios of the normal-to-superconducting transition in underdoped cuprates.
